Molecular mechanism of the ectodomain shedding of the NKG2D ligand MHC class I-related chain A in hepatocellular carcinoma and its therapeutic implication

• Project/Area Number: 20390208
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TAKEHARA Tetsuo Osaka University, 院医学系研究科, 教授 (70335355)
• Co-Investigator(Kenkyū-buntansha): TATSUMI Tomohide 大阪大学, 医学系研究科, 助教 (20397699)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2010: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2009: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2008: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 肝臓 / 癌 / 免疫 / NK細胞 / MICA / NKG2D / ADAM / ソラフェニブ / IL-1 / 炎症 / 肝癌 / C型肝炎 / MIC / sorafenib / 免疫治療 / 抗癌剤 / shedding

Research Abstract

MHC class I-related chain A (MICA), a ligand for the NKG2D activating receptor NKG2D, is expressed in hepatocellular carcinoma (HCC) and determines its sensitivity to NK cells. In the present study, we have shown that 1) the serum levels of soluble form of MICA increase in chronic liver disease and HCC as disease progresses, 2) ADAM9 and ADAM 10 are critically involved in shedding of MICA from HCC and 4) anti-tumor agents including sorafenib and epirubicin inhibit expression of ADA9 and ADAM 10, respectively, and shedding of MICA in HCC. These results indicate that ADAM family proteins are involved in ectodomain shedding of MICA from HCC and could be novel therapeutic targets for improving anti-tumor immune responses.

Research Products

• [Journal Article] ・-galactosylceramide activates antitumor immunity against liver tumor. (2011)
  • Author(s): Tatsumi T, Takehara T, Miyagi T, Sugiyama T, Aketa H, Sasakawa A, Kanto T, Hiramatsu N, Hayashi N.
  • Journal Title: Hepatol Res 41 Pages: 30-38
  • Peer Reviewed
• [Journal Article] Hepatitis C virus (HCV)-specific CD8+ T cell responses during pegylated interferon-alfa and ribavirin treatment are associated with the antiviral activity in patients with chronic hepatitis C virus infection. (2011)
  • Author(s): Tatsumi T, Takehara T, Miyagi T, Nakazuru S, Mita E, Kanto T, Hiramatsu N, Hayashi N.
  • Journal Title: Hepatol Res 41 Pages: 30-38
  • Peer Reviewed
• [Journal Article] Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet. (2010)
  • Author(s): Miyagi T, Takehara T, Uemura A, Nishio K, Shimizu S, Kodama T, Hikita H, Li W, Sasakawa A, Tatsumi T, Ohkawa K, Kanto T, Hiramatsu N, Hayashi N.
  • Journal Title: J Gastroenterol 45 Pages: 1247-1254
  • NAID: 10027700169
  • Peer Reviewed
• [Journal Article] Altered interferon-alpha-signaling in NK cells from the patients with chronic hepatitis C virus infection. (2010)
  • Author(s): Miyagi T, Takehara T, Nishio K, Shimizu S, Kohga K, Tatsumi T, Kanto T, Hiramatsu N, Hayashi N.
  • Journal Title: J Hepatol 53 Pages: 424-430
  • Peer Reviewed
• [Journal Article] Expression of CD133 confers malignant potential via inhibiting metalloproteinases in human hepatocellular carcinoma. (2010)
  • Author(s): Kohga K, Tatsumi T, Takehara T, Miyagi T, Hayashi N.
  • Journal Title: J Hepatol 52 Pages: 872-879
  • Peer Reviewed
• [Journal Article] Sorafenib inhibited the shedding of MICA on hepatocellular carcinoma cells by downregulating ADAM9. (2010)
  • Author(s): Kohga K, Takehara T, Tatsumi T, Ishida H, Miyagi T, Hosui A, Hayashi N.
  • Journal Title: Hepatology 51 Pages: 1264-1273
  • Peer Reviewed
• [Journal Article] EphA2-derived peptide vaccine with amphiphilic poly (γ-glutamic acid) nanoparticles elicits an antitumor effect against mouse liver tumor. (2010)
  • Author(s): Yamaguchi S, Tatsumi T, Takehara T, Sasakawa A, Yamamoto M, Kohga K, Miyagi T, Kanto T, Hiramatsu N, Akagi T, Akashi M, Hayashi N.
  • Journal Title: Cancer Immunol Immunother 59 Pages: 759-767
  • Peer Reviewed
• [Journal Article] Natural killer cell is a major producer of interferon・that is critical for the IL-12-induced anti-tumor effect in mice. (2010)
  • Author(s): Uemura A, Takehara T, Miyagi T, Suzuki T, Tatsumi T, Ohkawa K, Kanto T, Hiramatsu N, Hayashi N.
  • Journal Title: Cancer Immunol Immunother 59 Pages: 453-463
  • Peer Reviewed
• [Journal Article] Sorafenib inhibited the shedding of MICA on hepatocellular carcinoma cells by downregulating ADAM9. (2010)
  • Author(s): Kohga K, Takehara T, et al.
  • Journal Title: Hepatology Volume: 51 Pages: 1264-1273
  • Peer Reviewed
• [Journal Article] The Bcl-xL inhihitor, ABT-737.efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. (2010)
  • Author(s): Hikita H, Takehara T, et al.
  • Journal Title: Hepatology Volume: 52 Pages: 1310-1321
  • Peer Reviewed
• [Journal Article] The let-7 family of microRNAs negatively regulates Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. (2010)
  • Author(s): Shimizu S, Takehara T, et al.
  • Journal Title: J Hepatol Volume: 52 Pages: 698-704
  • Peer Reviewed
• [Journal Article] Natural killer cell is a major producer of interferon γ that is critical for the IL-12-induced anti-tumor effect in mice. (2010)
  • Author(s): Uemura A, Takehara T, et al.
  • Journal Title: Cancer Immunol Immunother 59 Pages: 453-463
  • Peer Reviewed
• [Journal Article] Anti-cancer therapy inhibits MICA ectodomain shedding by downregulating ADAM10 expression in hepatocellular carcinoma. (2009)
  • Author(s): Kohga K, Takehara T, Tatsumi T, Miyagi T, Ishida H, Ohkawa K, Kanto T, Hiramatsu N, Hayashi N.
  • Journal Title: Cancer Res 69 Pages: 8050-8057
  • Peer Reviewed
• [Journal Article] Activated liver dendritic cells generates strong acquired immunity in・-galactosylceramide treatment. (2009)
  • Author(s): Sasakawa A, Tatsumi T, Takehara T, Yamaguchi S, Yamamoto M, Ohkawa K, Miyagi T, Hayashi N.
  • Journal Title: J Hepatol 50 Pages: 1155-1162
  • Peer Reviewed
• [Journal Article] Anti-cancer therapy inhibits MICA ectodomain shedding by downregulatine ADAM10 expression in henatocellular carcinoma. (2009)
  • Author(s): Kohga K, Takehara T, et al.
  • Journal Title: Cancer Res 69 Pages: 8050-8057
  • Peer Reviewed
• [Journal Article] Decreased expressions of CDld molecule on liver dendritic cells in subcutaneous tumor bearing mice. (2008)
  • Author(s): Tatsumi T, Takehara T, Yamaguchi S, Sasakawa A, Yamamoto M, Fujita Y, Miyagi T, Ohkawa K, Hayashi N.
  • Journal Title: J Hepatol 49 Pages: 779-786
  • Peer Reviewed
• [Journal Article] Serum levels of soluble MHC class I-related chain A in patients with chronic liver diseases and the changes during transcatheter arterial embolization for hepatocellular carcinoma. (2008)
  • Author(s): Kohga K, Takehara T, Tatsumi T, Ohkawa K, Miyagi T, Hiramatsu N, Kanto T, Kasugai T, Katayama K, Kato M, Hayashi N.
  • Journal Title: Cancer Sci 99 Pages: 1643-1649
  • Peer Reviewed
• [Journal Article] Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity. (2008)
  • Author(s): Yamaguchi S, Tatsumi T, Takehara T, Sasakawa A, Hikita H, Kohga K, Uemura A, Sakamori R, Ohkawa K, Hayashi N.
  • Journal Title: Cancer Immunol Immunother 57 Pages: 1861-1869
  • Peer Reviewed
• [Journal Article] Declining incn, from 1990dence of hepatocellular carcinoma in Osaka, Japa0 2003. (2008)
  • Author(s): Tanaka H, Takehara T, etal.
  • Journal Title: Ann Intern Med 148 Pages: 820-826
  • Peer Reviewed
• [Journal Article] Serum levels of soluble MHC class I-related chain A in patients with chronic liver diseases and the changes during transcatheter arterial embolization for hepatocellular carcinoma. (2008)
  • Author(s): Kohga K, Takehara T, etal.
  • Journal Title: Cancer Sci 99 Pages: 1643-1649
  • Peer Reviewed
• [Journal Article] Decreased expressions of CDld molecule on liver dendritic cells in subcutaneous tuior bearing mice. (2008)
  • Author(s): Tatsumi T, Takehara T, et al.
  • Journal Title: J Hepatol 49 Pages: 779-786
  • Peer Reviewed
• [Journal Article] Differential alteration of CD56-bright and CD56-dim NK cells in frequency, phenotype and cytokine response in patients with chronic hepatitis C virus infection.
  • Author(s): Miyagi T, Shimizu S, Nishio K, Tatsumi T, Hiramatsu N, Kanto T, Hayashi N, Takehara T.
  • Journal Title: J Gastroenterol in press
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells.
  • Author(s): Tsunematsu H, Tatsumi T, Kohga K, Yamamoto M, Aketa H, Miyagi T, Hosui A, Hiramatsu N, Kanto T, Hayashi N, Takehara T.
  • Journal Title: Int J Cancer in press
  • Peer Reviewed
• [Presentation] The role of IFN-STAT1 signal transduction on inhibition of HCC development (2010)
  • Author(s): 法水淳, 竹原徹郎, et al.
  • Organizer: The Liver Meeting 2010
  • Place of Presentation: Boston Hynes Convention Center
• [Presentation] 「C型肝炎からの肝発がん」「IFN-STAT1活性化が肝癌進展に及ぼす影響の検討」「Sorafenibは肝細胞癌のADAM9を抑制することでMICAのsheddingを制御する」「CD133陽性肝細胞癌はmetalloproteinaseを制御しその生存に有利な環境を作る」 (2010)
  • Author(s): 竹原徹郎, 法水淳, 竹原徹郎, 他, 甲賀啓介, 竹原徹郎, 他, 巽智秀, 竹原徹郎, 他
  • Organizer: 第69回日本癌学会学術総会(シンポジウム2ウイルス発がん)
  • Place of Presentation: 大阪国際会議場リーガロイヤルホテル
• [Presentation] 「IFN-STAT1活性化が肝癌進展に及ぼす影響の検討」「a-fetoproteinによる先天免疫活性化抑制機構の解析」 (2010)
  • Author(s): 法水淳, 竹原徹郎, 他, 山本政司, 竹原徹郎, 他
  • Organizer: 第46回日本肝臓学会総会(シンポジウム2肝細胞癌の分子標的探索と臨床応用)
  • Place of Presentation: ホテルメトロポリタン山形、山形テルサ、山形国際ホテル
• [Presentation] 「肝細胞癌にけるNK活性化レセプターNKG2Dリガンドの発現とADAMファミリーによるその制御」「NAFLD病態におけるinvariant NKT細胞が果たす役割」 (2010)
  • Author(s): 甲賀啓介, 竹原徹郎, 他, 宮城琢也, 竹原徹郎, 他
  • Organizer: 第96回日本消化器病学会総会(シンポジウム7 C型肝炎:ウイルス感染の分子免疫機構)(ワークショップ3 NASH/NAFLD発症のメカニズム)
  • Place of Presentation: )新潟県民会館、新潟市民芸術文化会館、新潟市音楽文化会館、朱鷺メッセ
• [Presentation] ABT-737, a Bad mimetic Bcl-xL inhibitor. enhances the anti-tumor effect of sorafenib against hepatocellular carcinoma. (2010)
  • Author(s): Hikita H, Takehara T, et al.
  • Organizer: The Liver Meeting 2010
  • Place of Presentation: Boston, MA, USA
• [Presentation] α-galactosylceramideによる肝樹状細胞の活性化機構の解析 (2009)
  • Author(s): 笹川哲, 竹原徹郎, 他
  • Organizer: 第23回肝類洞壁細胞研究会学術集会
  • Place of Presentation: ホテル京阪ユニバーサルタワー(大阪)
• [Presentation] 「α-fetoprotein impairs NK activity by inhibiting dendritic cell function 」「Anti-cancer chemotherapy enhances NK sensitivity by inhibiting MICA ectodomain shedding in human hepatocellular carcinoma」 (2009)
  • Author(s): Yamamoto M, Takehara T, et al., Kohga K, Takehara T, et al.
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場
• [Presentation] 「Interferon-α-signaling in natural killer cells is impaired in chronic hepatitis C virus infection」「Lack of invariant natural killer T cells elicits liver inflammation and predisposes to liver fibrosis in mice fed with high-fat diet」 (2009)
  • Author(s): Miyagi T, Takehara T, et al., Nishio K, Takehara T, et al.
  • Organizer: The Liver Meeting 2009
  • Place of Presentation: Boston HYNES CONVENTION CENTER
• [Presentation] 非アルコール性脂肪性肝炎病態進展におけるInvariant NKT細胞の役割 (2009)
  • Author(s): 宮城琢也, 竹原徹郎, 他
  • Organizer: JDDW 2009(パネルディスカッション11自然免疫と消化器疾患)
  • Place of Presentation: 国立京都国際会館、グランドプリンスホテル京都
• [Presentation] α-fetoproteinによる免疫抑制-NK細胞による細胞障害活性について (2009)
  • Author(s): 山本政司, 竹原徹郎, 他
  • Organizer: 第45回日本肝癌研究会
  • Place of Presentation: 福岡国際会議場
• [Presentation] 「非アルコール性脂肪性肝炎病態形成におけるNKT細胞の関与」「肝細胞癌におけるNK活性化レセプターリガンドMICA分泌(shedding)の分子機構」「α-PGAナノ粒子を用いた癌免疫療法の基礎的検討」「肝細胞特異的STAT5欠損マウスにおける肝線維化・発がんの分子機構」 (2009)
  • Author(s): 宮城琢也, 竹原徹郎, 他, 甲賀啓介, 竹原徹郎, 他, 山口真二郎, 竹原徹郎, 他, 法水淳, 竹原徹郎, 他
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際展示場
• [Presentation] 「C型肝炎に対するIFN治療における免疫エフェクター細胞内シグナル伝達解析」「肝発癌過程におけるSTAT5の役割」 (2009)
  • Author(s): 宮城琢也, 竹原徹郎, 他, 法水淳, 竹原徹郎, 他
  • Organizer: 第95回日本消化器病学会総会(パネルディスカッション6 C型肝炎治療の最前線)(ワークショップ4肝細胞癌の予防)
  • Place of Presentation: 北海道厚生年金会館、ロイトン札幌、京王プラザホテル札幌
• [Presentation] 肝細胞癌におけるNK活性化レセプターリガンドMICA分泌(shedding)の分子機構 (2009)
  • Author(s): 甲賀啓介、竹原徹郎, 他
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: 神戸
• [Presentation] C型肝炎・肝がんの自然免疫病態 (2008)
  • Author(s): 竹原徹郎
  • Organizer: 肝疾患と代謝
  • Place of Presentation: 帝国ホテル大阪(特別講演)
  • Year and Date: 2008-10-09
• [Presentation] C型肝炎における持続感染・発がんと自然免疫病態 (2008)
  • Author(s): 竹原徹郎
  • Organizer: 第12回九州肝不全研究会
  • Place of Presentation: ソラリア西鉄ホテル(博多)(教育講演)
  • Year and Date: 2008-09-20
• [Presentation] C型肝炎の病態と自然免疫 (2008)
  • Author(s): 竹原徹郎
  • Organizer: 第45回日本消化器免疫学会総会
  • Place of Presentation: メルパルク京都(イブニングセミナー)
  • Year and Date: 2008-07-03
• [Presentation] Regulation of NKG2D immunoreceptor by soluble form of MHC class I-related chain A in hepatocellular carcinoma (2008)
  • Author(s): 竹原徹郎
  • Organizer: 13^<th> US-Japan GI & Liver Meeting in 21st Century
  • Place of Presentation: Sheraton Miyako Hotel Tokyo
  • Year and Date: 2008-06-13
• [Presentation] 「NK cell expression of NKG2D is impaired in patients with chronic hepatitis C」「Immunotherapy with gamma poly-glutamic acid nanoparticles in mouse liver tumor」 (2008)
  • Author(s): Shimizu S, Yamaguchi S, Takehara T, et al.
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] 「EFFICACY OF THE IMMUNOTHERAPY WITH POLYγ-GLUTAMIC ACID NANOPARTICLES IN MOUSE LIVER TUMOR」「EXPRESSION OF NKG2D ACTIVATING RECEPTOR ON NATURAL KILLER CELLS IN CHRONIC HEPATITIS C」「ACTIVATED LIVER DENDRITIC CELLS ARE MORE IMMUNOGENIC THAN SPLEEN DENDRITIC CELLS AFTER α-GALCER TREATMENT」「SN38 INHIBITS SHEDDING OF MHC CLASS1-RELATED CHAIN A, A LIGAND OF NKG2D IMMUNORECEPTOR IN HUMAN HEPATOCELLULAR CARCINOMA CELLS」 (2008)
  • Author(s): Yamaguchi S, Takehara T, et al., Shimizu S, Takehara T, et al., Sasakawa A, Takehara T, et al., Kohga K, Takehara T, et al.
  • Organizer: The Liver Meeting 2008
  • Place of Presentation: San Francisco, Moscone West Convention Center
• [Presentation] C型肝炎に対するインターフェロン治療における免疫細胞内シグナル伝達解析による治療効果予測の可能性 (2008)
  • Author(s): 宮城琢也, 竹原徹郎, 他
  • Organizer: JDDW 2008
  • Place of Presentation: グランドプリンスホテル新高輪、国際館パミール、グランドプリンスホテル高輪(シンポジウム14 C型肝炎の近未来治療)
• [Presentation] 「SN38は肝癌細胞の可溶型NK活性リガンドの分泌を抑制しNK細胞感受性を増強させる」「IL-12遺伝子による肝臓NK細胞の活性化および転移性肝腫瘍の治療効果にはリンパ球からのIFN・の産生が重要である」「皮下腫瘍担癌マウスにおける肝樹状細胞上CD1d分子発現低下による肝先天免疫の抑制」「肝先天免疫活性化による肝樹状細胞活性化機構の解析」「ウイルス感染モデルを用いたインターフェロンの免疫細胞内におけるシグナル伝達機構の制御メカニズムに関する基礎的検討」 (2008)
  • Author(s): 甲賀啓介, 竹原徹郎, 他, 植村彰夫, 竹原徹郎, 他, 巽智秀, 竹原徹郎, 他, 笹川哲, 竹原徹郎, 他, 宮城琢也, 竹原徹郎, 他
  • Organizer: 第44回日本肝臓学会総会
  • Place of Presentation: 愛媛県県民文化会館、愛媛看護研修センター(松山)(ワークショップ3肝の発癌と進展における分子代謝学的研究)
• [Presentation] SN38は肝癌細胞のNK細胞感受性を増強させる (2008)
  • Author(s): 甲賀啓介, 竹原徹郎, 他
  • Organizer: 第44回日本肝癌研究会
  • Place of Presentation: 大阪国際会議場
• [Presentation] NK細胞による肝癌認識機構の分子機序の解析と新規治療法の探索 (2008)
  • Author(s): 竹原徹郎
  • Organizer: 第94回日本消化器病学会総会
  • Place of Presentation: 福岡国際会議場、福岡サンパレス、マリンメッセ福岡(シンポジウム9ウイルス肝炎・肝癌に対する生体防御)
• [Presentation] SN38 INHIBITS SHEDDING OF MHC CLASS1-RELATED CHAIN A, A LIGANDOF NKG2D IMMUNORECEPTOR IN HUMAN HEPATOCELLULAR CARCINOMA CELLS. (2008)
  • Author(s): Kohga K, Takehara T, etal.
  • Organizer: The American Association for the study of Liver Diseases, 59th Annual Meeting AASLD
  • Place of Presentation: San Francisco (DSA)
• [Book] 肝胆膵領域(NK細胞による肝癌認識機構の分子機序の解析と新規治療法の探索.消化器病学の進歩-原点から未来への情報発信-II)(編集 飯田三雄 発行)(東京) (2009)
  • Author(s): 竹原徹郎
  • Publisher: 日本消化器病学会
• [Remarks] ホームページ等
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